[unreadable] Colorectal cancer remains the second leading cause of cancer death in the United States. Since most of the American population fails to receive any kind of screening because of significant constraints from a health care delivery point of view, targeted colonoscopy to patients at elevated risk of colon cancer may be the most practical approach to pursue. Given that colorectal cancer represents a "field defect", identification of markers in the uninvolved colonic mucosa may represent an excellent method of risk-stratification. The ideal biomarker would be easily obtained from the patient with high sensitivity and positive predictive value. Numerous putative biomarkers have been proposed, but they have all lacked either sensitivity or have unacceptably high false positive rate thus making them suboptimal for clinical practice. Furthermore, these biomarkers are often insensitive to the molecular alterations in colon carcinogenesis. Recently, several lines of evidence suggest that micro-structural changes can be detected at very early time points and therefore may represent a promising intermediate biomarker. These abnormalities may occur at several levels including chromatin texture, nuclear size, ploidy, etc. However, detection of these abnormalities in situ requires novel techniques. We have recently pioneered light scattering spectroscopy (LSS) as a novel optical technology to probe the structure of living epithelial cells. This technique utilizes spectral analysis of the elastically scattered light to quantify tissue structure at scales ranging from the tens of nanometers (size of large macromolecular complexes) to several microns (size of cells and their nuclei). We hypothesize that distinct LSS signatures will be detectable in the premalignant mucosa and will be able to predict the development of colon cancers. These signatures will be used to establish how the cell organization and molecular events are interrelated and affect the development of cancer. Specifically, we will establish the spectroscopic signatures of macroscopically-normal colon mucosa during various stages of carcinogenesis using the carcinogen-treated rat model and evaluate LSS signatures in relation to time and dosage of carcinogen administration. The special emphasis will be on the characterization of the alterations of the nano/micro-architecture of living epithelial cell. Moreover, we will correlate these LSS signatures with occurrence of molecular and cellular changes important in the early stages of colon carcinogenesis. Furthermore, we will evaluate the ability of LSS to detect alterations in key signatures by an established non-steroidal anti-inflammatory chemopreventive agent, sulindac. Our future directions would be to use this data to develop an instrument that could assess rectal mucosa LSS to identify patients at highest risk for colon cancer and target them for colonoscopy. [unreadable] [unreadable]